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E3 Ubiquitin Ligase c-cbl Inhibits Microglia Activation After Chronic Constriction Injury

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Abstract

E3 ubiquitin ligase c-Caritas B cell lymphoma (c-cbl) is associated with negative regulation of receptor tyrosine kinases, signal transduction of antigens and cytokine receptors, and immune response. However, the expression and function of c-cbl in the regulation of neuropathic pain after chronic constriction injury (CCI) are unknown. In rat CCI model, c-cbl inhibited the activation of spinal cord microglia and the release of pro-inflammatory factors including tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6), which alleviated mechanical and heat pain through down-regulating extracellular signal-regulated kinase (ERK) pathway. Additionally, exogenous TNF-α inhibited c-cbl protein level vice versa. In the primary microglia transfected with c-cbl siRNA, when treated with TNF-α or TNF-α inhibitor, the corresponding secretion of IL-1β and IL-6 did not change. In summary, CCI down-regulated c-cbl expression and induced the activation of microglia, then activated microglia released inflammatory factors via ERK signaling to cause pain. Our data might supply a novel molecular target for the therapy of CCI-induced neuropathic pain.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 81501076, 81401365), the Science and Technology of construction and people’s livelihood Foundation of Jiangsu Province (BL2014061), Jiangsu Province Young Medical Key Talents Project of China (QNRC2016407), the Nantong Science and Technology Innovation Project (No. MS12015056); and the 14th Six Talents Peak Project of Jiangsu Province (No. SWYY-058), and National Natural Youth Science Fund (No. 81702216).

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  1. Pengfei Xue and Xiaojuan Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Spine Surgery, the Second Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, China

    Pengfei Xue, Xiongsong Lu, Jinlong Zhang, Guanhua Xu, Yuyu Sun, Jiajia Chen, Haiyan Gu, Zhiming Cui & Guofeng Bao

  2. Department of Pathogen Biology, Medical College, Nantong University, Nantong, 226001, Jiangsu, China

    Xiaojuan Liu

  3. Department of Cardiology, Affiliated Hospital of Nantong University, Nantong, 226001, China

    Yiming Shen

  4. Medical College, Nantong University, Nantong, 226001, Jiangsu, China

    Yuanyuan Ju

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  1. Pengfei Xue
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Xue, P., Liu, X., Shen, Y. et al. E3 Ubiquitin Ligase c-cbl Inhibits Microglia Activation After Chronic Constriction Injury. Neurochem Res 43, 1631–1640 (2018). https://doi.org/10.1007/s11064-018-2578-8

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